ALBERT

Description: Although diffuse large B cell lymphoma (DLBCL) cells widely express the BCL2 protein, they rarely respond to treatment with BCL2-selective inhibitors. Here we show that DLBCL cells harboring PMAIP1/NOXA gene amplification were highly sensitive to BCL2 small-molecule inhibitors. In these cells, BCL2 inhibition induced cell death by activating caspase 9, which was further amplified by caspase-dependent cleavage and depletion of MCL1. In DLBCL cells lacking NOXA amplification, BCL2 inhibition was associated with an increase in MCL1 protein abundance in a BIM-dependent manner, causing a decreased antilymphoma efficacy. In these cells, dual inhibition of MCL1 and BCL2 was required for enhanced killing. Pharmacologic induction of NOXA, using the histone deacetylase inhibitor panobinostat, decreased MCL1 protein abundance and increased lymphoma cell vulnerability to BCL2 inhibitors in vitro and in vivo. Our data provide a mechanistic rationale for combination strategies to disrupt lymphoma cell codependency on BCL2 and MCL1 proteins in DLBCL.

Description: The PIM kinases are highly expressed in activated B-cell (ABC) diffuse large B-cell lymphoma (DLBCL). Oncogenic cooperation between PIMs and MYC has been demonstrated. Transgenic mice co-expressing Em-PIM and Em-MYC showed accelerated lymphomagenesis. Conversely, knockdown of PIMs dramatically decreased cMYC levels and lowered tumor incidence. Based on these preclinical data, a treatment strategy aiming at disrupting the oncogenic cooperation between PIMs and MYC may improve the outcome of DLBCL. Therefore, we treated a panel of DLBCL cell lines with increasing dose of the clinically relevant pan-PIM inhibitor (PIMi) AZD1208 (from 0.1 to 10μM) for 48 hours (Hrs), which resulted in a dose-dependent growth inhibition with a stronger efficacy in ABC DLBCL cell lines. (Figure 1A)The analysis of a CRISPR loss-of-function screening in three ABC (LY3, TMD8, HBL1) and three GCB (SUDHL-4, Pfeiffer, BJAB) DLBCL cell lines (Reddy et al, 2017) showed that PIM2 silencing led to significantly decreased viability irrespective of cell-of-origin (Figure 1B), suggesting that this oncogene is essential for cell proliferation in DLBCLs. To identify the genes through which PIMs drive the lymphoma phenotype we performed gene expression profiling using 4 ABC DLBCL cell lines (RIVA, TMD8, SUDHL-2, U2932) treated with either DMSO or AZD1208 at 1μM for 4, 8 and 12 Hrs. We observed induction of 3,439 genes whereas 2,473 genes were downregulated. (Figure 1C) Gene pathway analysis showed that AZD1208 led to downregulation of genes regulated by MYC, including its known downstream p53 and NFKB target genes. On the other hand, AZD1208 treatment broadly induced MHC class II and antigen presentation genes as well as PI3K/AKT, cell cycle and glutaminase genes. (Figure 1D) Using a high-throughput screening approach, we found that the inhibitors of cell cycle (such as the BCL2 inhibitor venetoclax/ABT199 and the PLK4 inhibitor CFI-400945) and of glutaminase (CB839) enhanced the antiproliferative effect of AZD1208, whereas combinations with the PI3K/AKT/mTOR inhibitors had negligible synergistic effect. (Figure 1E) In conclusion, our study revealed previously unknown mechanisms of action of PIM inhibitors and provides a framework for future combination strategies. Disclosures Younes: Xynomics: Consultancy; Biopath: Consultancy; Genentech: Research Funding; AstraZeneca: Research Funding; Syndax: Research Funding; BMS: Research Funding; HCM: Consultancy; Celgene: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Takeda: Honoraria; Roche: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Curis: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Abbvie: Honoraria; Pharmacyclics: Research Funding. Bertoni:Nordic Nanovector ASA: Research Funding; Acerta: Research Funding; ADC Therapeutics: Research Funding; Bayer AG: Research Funding; Cellestia: Research Funding; CTI Life Sciences: Research Funding; EMD Serono: Research Funding; Helsinn: Consultancy, Research Funding; ImmunoGen: Research Funding; Menarini Ricerche: Consultancy, Research Funding; NEOMED Therapeutics 1: Research Funding; Oncology Therapeutic Development: Research Funding; PIQUR Therapeutics AG: Other: travel grant, Research Funding; HTG: Other: Expert Statements ; Amgen: Other: travel grants; Astra Zeneca: Other: travel grants; Jazz Pharmaceuticals: Other: travel grants.

Description: Chronic Lymphocytic Leukemia (B-CLL) is the most prevalent adult leukemia in western countries, with a median age of onset of 65 years. Front-line therapy for B-CLL young patients is chemo-immunotherapy with Fludarabine-Cyclophosphamide and Rituximab (FCR). However, many B-CLL patients are elderly and with comorbidities. FCR regimen can result in a significant myelosuppression and a high rate of early and late infections, suggesting that it may be too toxic and therefore unsuitable for this large subpopulation of patients. Data from the CLL 5 phase III trial of the German CLL study group (GCLLSG) comparing Fludarabine vs Chlorambucil (Chl) in patients older than 65 years showed no differences in overall survival and progression free survival (PFS) between Fludarabine and Chl. Recently, Bendamustine as single agent showed superiority in comparison to Chl in terms of overall response rate (ORR) and PFS, with a good safety profile. Later, the addition of Rituximab (RTX) to Bendamustine (Benda-R) was shown to be efficacious and safe in the same treatment-naïve setting. Insufficient data are available in patients older than 70 years regarding the efficacy and safety, nevertheless increased incidence of extra-hematological toxicity was noted in this subgroup. Here we report our multicentre retrospective study focusing on responses and toxicities rate in elderly patients with B-CLL. We report data on 24 elderly patients with previously untreated B-CLL observed in 7 Italian Centers from November 2000 to June 2012. All patients were treated with a median of 6 cycles of Bendamustine (range, 3-6) at the median dose of 90 mg/m2 (range, 70-90 mg/m2) for 2 consecutive days every 28 days plus RTX (375 mg/m2 for the first course and 500 mg/m2 for subsequent cycles every 28 days). The median number of RTX cycles was 6 (range, 3-6). The mean dose of RTX was 4500 mg (range, 1500-6200 mg). The primary end points were the ORR (complete response CR and partial response PR) and hematological-extrahematological toxicities rate. Twenty male and four female with a median age of 72 years (range, 65-87 years) were included in the study. Only one patient was unfit with a CIRS score of 7. All patients had ECOG less than 2. Two B-CLL patients had A/I progressive stage according Binet and Rai, 10 patients had B/II and 12 patients had C/III or C/IV. The median lymphocytes count at diagnosis was 37.040/mmc (range, 2.200-140.000). FISH analysis was performed in 19/25 patients: 12 patients were classified as standard risk (normal karyotype, del13q14 or +12) and 7 patients as high risk (del11q and del17p). The analysis of the IgVH, available in 12 patients, showed 7 patients with somatic mutation and 5 patients with germ-line sequences. Only one patient was admitted to the hospital and one received reduced bendamustine dose for neutropenia. Fifteen patients received bendamustine at the dosage of 90 mg/m2 while 9 were treated with 70 mg/m2. The ORR rate was 87.5%: ten patients (41.7%) obtained a complete response and eleven patients (45.8%) obtained a partial response. Among biological features the presence of standard risk FISH karyotype showed a statistical significance in terms of better response to therapy (p= 0.013) and progression (p=0.034). Hematological toxicity was recorded in 7 patients (29%) (neutropenia grade III/IV), 5 of them required G-CSF. Extra-hematological toxicity grade I-III was noticed in 8 patients (3 skin reactions, 3 infusion related reactions, 2 nausea and vomiting). At the present only four patients showed a progressive disease with a PFS of 92% at 12 months. Only one unresponsive patient died from Richter disease 6 months after the end of therapy. When we stratified patients in two groups according to the age, we found that patients younger than 75 years (15 patients) showed a better response (p=0.004) and a delayed time to progression (p=0.027) in comparison to patients more than 75 years. Retrospective data from this group of elderly B-CLL patients indicate Benda-R front-line provide a high response rate and a good safety profile. Also in a subgroup of very elderly patients (age 〉 75 years) the association of bendamustine 90 mg/m2 and rituximab at standard dose is recommended because of a low rate of dose delay/reduction and acceptable hematological/extrahematological toxicities. Disclosures: No relevant conflicts of interest to declare.

Description: Background: Despite the important progress in the research of myeloproliferative neoplasms (MPN) in the last years, treatment options are still limited. Currently, a cytoreductive approach is the backbone treatment, with hydroxyurea (HU) being the most important agent. However, this drug is not always well tolerated and seems to be associated with a potential leukemogenic effect. A valid alternative treatment is interferon alfa (IFN-α), but is reserved for selected patients due to the unfavorable toxicity profile. Furthermore, studies directly comparing IFN-α to HU are lacking, which is why we performed the so far largest Philadelphia negative (Ph-) MPN real-life analysis. Methods: From 2000 to January 2016 we prospectively assessed 63 Ph- MPN patients who received either HU at induction dosage of 25 mg/kg daily until achievement of hematologic remission, followed by maintenance therapy at 10 to 15 mg/kg daily, or IFN-α 3 MU subcutaneously three times a week. The treatment was selected based on physician's choice. All patients were screened for molecular genetic and cytogenetic analysis at diagnosis and during treatment. Results: Between January 2000 and January 2016, 63 consecutive patients were diagnosed with Ph- MPN: 28 were affected by polycythemia vera (PV) and 35 by essential thrombocytosis (ET). Fifteen patients with PV (54%) and 20 with ET (57%) were treated with IFN-α, while 13 with PV (46%) and 15 with ET (43%) received HU, respectively. Clinical characteristics were similar between both treatment groups and no significant differences were observed. During a median follow-up period of 81 months (range, 48-168 months) 97% of the patients treated with IFN-α achieved a hematologic response [60% complete (CHR), 37% partial (PHR)] compared to 78% in HU group (56% CHR, 20% PHR; p〈 0.01). Molecular responses were limited to patients treated with IFN-α. Among these, the overall molecular response rate was 60% in both PV and ET. Complete molecular response (CMR) was achieved in 20% patients with PV and in 10% with ET, whereas partial molecular response (PMR) in 33% and 20% of patients with PV and ET, respectively. (Fig.1) Importantly, no patient who achieved CMR was observed to experience hematologic or molecular relapse after a median follow up of 92 months (range 53-132 months), suggesting that this drug is able to modify the natural course of Ph- MPN. In contrast, HU did not influence molecular response. In addition to molecular genetic analysis, we performed conventional cytogenetics on all patients at diagnosis and during treatment. Six patients were found to have abnormalities on metaphase cytogenetics pretreatment with IFN-α. Of these 6 patients, 1 had a resolution of cytogenetic abnormalities during the study. We did not observe the acquisition of new cytogenetic abnormalities in these 6 patients or in the others with normal baseline cytogenetics during therapy. Four patients were found having cytogenetic abnormalities before HU and two more developed new abnormalities over the course of the treatment, suggesting that this drug is not able to prevent leukemogenesis. IFN-α was well tolerated with no secondary malignancy, while HU was associated with more toxic events and seemed to increase risk of leukemia. Conclusion: We provide evidence that IFN-α might be a more valid therapeutic option due to its more profound hematologic responses, the ability to induce molecular responses and the potential ability to reduce the risk of leukemic transformation. Disclosures No relevant conflicts of interest to declare.

Description: Background: Follicular lymphoma (FL) is the most frequent indolent lymphoma. While immunochemotherapy (IC) treated FL patients who achieve event-free status at 24 months after diagnosis (EFS24) have the subsequent life expectancy of the general population, those who fail to achieve EFS24 have aggressive disease with poor outcomes. Similarly, in FL patients initially observed or treated with rituximab monotherapy, EFS at 12 months (EFS12) is a strong predictor of subsequent outcome. Thus, an unmet patient need is to predict at diagnosis those at greatest risk of early failure in order to identify better treatments. The lymphoma microenvironment may be a key determinant of early failure. Therefore, we aimed to improve risk stratification of newly diagnosed FL patients by using a discovery and validation study design to identify microenvironment determinants of early failure and then integrate them into the Follicular Lymphoma International Prognostic Index (FLIPI). Patients and Methods: We evaluated 496 patients with FL grade 1-3A who were prospectively enrolled into the Molecular Epidemiology Resource (MER) cohort from 2002-2012. In the discovery set of patients (N=166), we stained tissue microarrays for CD4, CD8, FOXP3, CD32b, CD14, CD68, CD70, SIRPa, TIM3, PD-1 and PDL1. Immunohistochemical staining was determined both within and between malignant follicles. Stains were scored to the nearest decile as the percentages of cells positive. Scores for each stain were dichotomized as 0% vs 〉0% except for CD32b (

Description: Background Biosimilar drugs have a similar, but usually not inferior although not hidentical effects of old registred drugs. Safety is hidentical to old registred drug. Aims Aim of this study is to verify if in MDS patient with refractory anemia biosimilar erythropoietin alpha is not inferior to erythropoietin alpha in terms of safety, efficacy and costs. Methods This study is a dicentric, nonrandomized, retrospective study. Between july 2008 and june 2012, 92 patients affected by refractory anemia were studied. Median follow-up was 22 months (R3-34). Patients received in group A erythropoietin alpha 40000 IU sc/weekly. In group B patient received biosimilar erythropoietin alpha 40000 IU sc/weekly. In both groups patients received liposomal iron (Sideral®) 14 mg, 2 tablets orally/day calcium levofolinate 7.5 mg/day orally + Vitamin B12: 400 mg/day orally. In group A median age was 70 years (R63-75), M/F: 18/28; in group B median age was 64 years (R60-70), M/F: 25/21. IPSS was low in 30 patients and int-1 in 13 patients in group A, and low in 32 patients and int-1 in 11 patients, in group B. Patients with 5q- were excluded from this study. Median level of haemoglobin was 8.5 g/dl in group A (R8-11) and 9.2 g/dl (R8.5-11.5) in group B. Results Group A patients increased Hb level of 1 g/dl after a median time of 5 weeks (R4-9) and after a median time of 4 weeks (R3-8) in group B. No relevant side effects were observed in both groups. Erythropoietin alpha was reduced in group A because Hb achieved a level 〉 12g/dl after a median of 12 weeks (R 4-18). Biosimilar erythropoietin alpha was reduced in group B because Hb achieved a level 〉 12g/dl after a median of 10.5 weeks (R 3-16). In group A maintenance dose was administered with a median of every two weeks (2-4), In group B maintenance dose was administered with a median of every three weeks (2-5). Median cost for every month of erythropoietic therapy was 1536 euros/month (R1240-1850) in group A and 1354 euros/month (R954-1550) in group B. Five patients need transfusion support in group A and seven patients need transfusion support in group B Summary/conclusion Biosimilar erythropoietin alpha plus liposomal iron (Sideral®) and B12 and folates support seems to be safe, feasible, probably equally cost-effective and substantially not inferior to classical erythropoietin alpha support in patients affected by refractory anemia. This study needs confifrmation on a larger cohort of patients. Disclosures No relevant conflicts of interest to declare.

Description: Background Biosimilar drugs, including erythropoirtin zed, have a similar, but usually not inferior although not hidentical effects of originator drugs. Safety is hidentical to originator drugs. Aims Aim of this study is to verify if in MDS patient with refractory anemia biosimilar erythropoietin alpha and erythropoietin zed, are not inferior to erythropoietin alpha in terms of safety, efficacy and costs. Methods This study is a retrospective study.Between july 2008 and december 2013, 101 patients affected by refractory anemia were studied.Median follow-up was 16 months (R10-28). Patients received in group A erythropoietin alpha 40000 IU sc/weekly. In group B patient received biosimilar erythropoietin alpha 40000 IU sc/weekly. In group C patient received biosimilar erythropoietin zed 40000 IU sc/weekly. In all three arms patients received liposomial iron (Sideral®) 14 mg 2 tablets orally/day calcium levofolinate 7.5 mg/day orally + Vitamin B12: 400 mg/day orally. In group A median age was 70 years (R63-73), M/F: 15/28. In group B median age was 64 years (R60-70), M/F: 24/19. In group C median age was 68 years (R62-73), M/F: 10/5.IPSS was low in 30 patients and int-1 in 12 patients, karyotype showed –Y in two patient, del 20q in one patient, trisomy 8 in two patients in group A. IPSS was low in 32 patients and int-1 in 10 patients, karyotype showed –Y in one patients, del 20q in one patient in group B.IPSS was low in 11 patients and int-1 in 4 patients, karyotype was normal in 9 patients and not evaluable in 6 patients. Patients with 5q- were excluded from this study. Median level of haemoglobin was 9 g/dl in group A (R8-11), 8.7 g/dl (R8.5-10.5) in group B and 8.5 in group C. Cost of every month of erythropoietinic therapy was calculed dividing for each patient the sum of complete erythropoietic therapy for each month of follow-up, then in each group of patients median cost of erythropoietic therapy was calculed. Results Group A patients increased Hb level of 1 g/dl after a median time of 5 weeks (R4-9), after a median time of 3.5 weeks (R3-8) in group B and after a memedian time of 4 weeks in group C. No relevant side effects were observed in all three groups groups. Erythropoietin alpha was reduced in group A because Hb achieved a level 〉 12g/dl after a median of 12 weeks (R 4-18).Biosimilar erythropoietin alpha was reduced in group B because Hb achieved a level 〉 12g/dl after a median of 10 weeks (R 3-16). Erythropoietin zed was reduced in group C because Hb achieved a level 〉 12g/dl after a median of 9.5 weeks (R 3-15). In group A maintenance dose was administered with a median of every two weeks (2-4), in group B maintenance dose was administered with a median of every three weeks (2-5), in group C maintenance dose was administered with a median of every three weeks (2-4). Median cost for every month of erythropoietic therapy was 1536 euros/month (R1240-1850) in group A, 1354 euros/month (R954-1550) in group B, 1300 euros/month (R1300-1380) in group C. Five patients need transfusion support in group A,6 patients need transfusion support in group B and 5 in group C. Summary/Conclusion Biosimilar erythropoietin alpha and erythropoietin zed plus liposomial iron (Sideral®) and B12 and folates support seems to be safe, feasible, probably equally cost-effective and substantially not inferior to classical erythropoietin alpha support in patients affected by refractory anemia. This study needs confifrmation on a larger cohort of patients. Disclosures No relevant conflicts of interest to declare.

Description: MYC overexpression is a poor prognostic predictor in Diffuse Large B-Cell Lymphoma (DLBCL). MYC-targeting with bromodomain and extraterminal protein family (BET) inhibitors is a promising strategy for the treatment of MYC-driven cancers, including lymphomas. However, preclinical and emerging data from early clinical trials demonstrated a modest antiproliferative activity in vitro and in vivo. We hypothesized that BET inhibition may induce feedback survival mechanisms preventing or attenuating cell death that could be exploited for designing future, more effective, combination strategies. In a high-throughput combinatorial drug screening experiment, we found that phosphatidylinositol 3-kinase (PI3K) pathway inhibitors enhanced the antiproliferative effects of BET inhibitors (JQ1, I-BET 151, CPI-203) with a strong class effect. JQ1 upregulated the mRNA expression of several upstream components of the PI3K pathway, including PIK3CA, PIK3R1, PDK1 in a large panel of DLBCL and Burkitt lymphoma cell lines. These effects translated in increased pathway activation as demonstrated by increased levels of the phosphorylated forms of downstream targets GSK3α/β, TSC2, P70S6K, and by increased concentrations of chemokines known to be regulated by PI3K in cell culture supernatants (CCL3 and CCL4). This effect was reversed by submicromolar doses of the PI3K inhibitor BKM-120. MYC silencing recapitulated the effects of BET inhibitors on PI3K pathway gene expression, activation and chemokine secretion. These data indicate that BET inhibition induces PI3K activation by a MYC-dependent feedback. We also observed transcriptional upregulation of the antiapoptotic gene Myeloid Leukemia 1 (MCL-1) following BET inhibition or MYC depletion, suggesting a second MYC-dependent mechanism. RNAi-mediated MCL-1 silencing or co-treatment with a small molecule MCL-1 inhibitor (UMI-77) enhanced the effects of BET inhibitors in DLBCL cell lines by inducing apoptosis. Using SILAC-based quantitative mass spectrometry, we found that BET inhibitors at submicromolar doses downregulated several E2 ubiquitin conjugating enzymes including UBE2C. RNAi mediated UBE2C knockdown induced MCL-1 upregulation in DLBCL cells. The enhanced in vitro effect of combining BETi and PI3Ki was reproduced in TMD8 mouse xenografts. To our knowledge, this is the first study demonstrating MYC-dependent regulation of the PI3K pathway, MCL-1 and the ubiquitin system upon BET inhibition. Our study revealed previously unknown mechanisms of action of BET inhibitors uncovering novel MYC-dependent survival feedback loops, and providing a framework for future combination strategies. Disclosures Zelenetz: Gilead Sciences: Research Funding.

Description: The front-line therapy for CLL young and fit patients is chemo-immunotherapy with Fludarabine-Cyclophosphamide and Rituximab (FCR). However, around three quarter of the patients with a newly diagnosed CLL are 65 years or older, with approximately 42% being older than 75 years and with age-related comorbidities. FCR regimen results in a significant myelosuppression and high rates of early and late infections. Hence, other less toxic regimens are under evaluation. Recently the German CLL study group reported an interim analysis of the CLL10 trial, who compared FCR vs Bendamustine-Rituximab (BR). The response rates to the 1st-line treatment with BR or FCR were comparable, and BR could be an alternative 1st-line treatment for medically fit pts. Notably, this study showed that pts treated with BR were often older (median 71 vs. 65 yrs; p 7). All patients had an ECOG performance status ranging from 0 to 2. Twenty-nine of 70 patients had Binet stage C, 12 patients were Binet A, 29 Binet B. Thirty-nine patients showed karyotype abnormalities at FISH analysis (data available in 54/70 patients). High risk FISH karyotype according to Döhner´s hierarchical model was detected in 17 patients (14 with del 11q, 3 with del 17p). Ten of them had del(13q14), 12 had trisomy 12 and 15 had normal karyotype. The analysis of the IGHV status, available in 50 patients, showed 25 patients with somatic mutation and 25 patients with germ-line sequences. Zap-70 data were available for 37/70 pts, 19 of them (51.3%) were Zap-70 positive. CD38 was available for 52 patients: it was positive in 27/52 pts (51.9%). (Table 1) A mean number of 5.46 courses of BR were given and the Bendamustine dose was reduced by more than 10% in 39 patients (55,7%). The main reason for dose reduction was haematological toxicities. The ORR rate was 88,6%,with 22 patients (31.4%) obtaining a CR and 40 patients (57,2%) obtaining a PR. Progression Free Survival, Time To Retreatment and Overall Survival rates at 2-years were 79%, 90.3% and 89.6%, respectively. Only the presence of del17 resulted to affect the response rate (p= 0.023) and PFS (p7 8/70 pts (11.4%) PB lymphocytes 33.203/mmc Binet stage A 12/70 pts (17.2%) Binet stage B 29/70 pts (41.4%) Binet stage C 29/70 pts (41.4%) ZAP70〉20% 19/37 pts (51.3 %) CD38〉 30% 27/52 pts (51.9%) Beta2microglobulin increased 51/59 pts (86.4%) IgVH homology 〈 98% 25/50 pts (50%) Normal FISH 15/54 pts (27.8%) del 13q 10/54 pts (18.5%) +12 12/54 pts (22.2%) del 11q 14/54 pts (25.9%) del 17p 3/54 pts (5.6%) Bulky syndrome 16/70 pts (22.9%) PB, peripheral blood; IgVH, immunoglobulin heavy chain variable genes; FISH, Fluorescent In Situ Hybridization. Disclosures No relevant conflicts of interest to declare.

Description: Oncogenic co-operation between c-Myc and activated phosphoinositide 3-kinase (PI3K) signaling pathways is crucial in lymphomagenesis, providing an opportunity for developing mechanism-based therapy to disrupt this co-operative survival mechanism. Combining constitutive c-Myc expression with constitutive PI3K activity in mouse germinal center B (GCB) cells resulted in Burkitt lymphoma-like tumors. Furthermore, analysis of primary human Burkitt lymphoma (BL) tissue sections revealed that two-thirds of the cases expressed high levels of phosphorylated AKT and S6 proteins, indicative of PI3K and mTORC1 activation. Prior attempts to develop small molecule inhibitors that specifically and directly target c-Myc protein have been unsuccessful. However, c-Myc cellular protein abundance can be decreased by using epigenetic modifying drugs (HDAC inhibitors or bromodomain/BET inhibitors) that are known to inhibit c-Myc transcription. Several investigators attempted disrupting c-Myc and PI3K cooperation by combining HDAC inhibitors and PI3K pathway inhibitors and synergic activity was demonstrated in DLBCL irrespective of subtype. In this study, we assessed the efficacy of CUDC-907, a new rationally designed dual inhibitor of PI3K and HDACs, in a panel of lymphoma cell lines. CUDC-907 treatment resulted in a dose- and time-dependent growth inhibition and cell death of DLBCL cell lines, irrespective of the cell of origin. CUDC-907 treatment down-regulated the phosphorylation of PI3K downstream targets, including AKT, PRAS40, S6, and 4EBP1, increased histone 3 acetylation, and decreased Myc protein levels. SILAC-based quantitative mass spectrometry demonstrated that CUDC-907 treatment decreased the protein levels of several components of the B cell receptor (BCR) and Toll like receptor (TLR) pathways, including BTK, SYK, and MyD88 proteins. These cellular changes were associated with an inhibition of NF-kB activation. CUDC-907 demonstrated in vivo efficacy with no significant toxicity in a human DLBCL xenograft mouse model. Collectively, these data provide a mechanistic rationale for evaluating CUDC-907 for the treatment of patients with c-Myc and PI3K-dependent lymphomas. Disclosures No relevant conflicts of interest to declare.